Piperazine derivatives

ABSTRACT

Piperazine derivatives of formula ##STR1## and their pharmaceutically acceptable acid addition salts are disclosed. In the formula n is 1 or 2, R is hydrogen or lower alkyl, R 1  is an aryl or nitrogen containing heteroaryl radical, R 2  is hydrogen or lower alkyl, R 3  is aryl, C 4-8  alkyl or aryl(lower)alkyl, and X is a functionalised group of specified meaning. The compounds exhibit activity as 5-HT 1A  antagonists and can be used, inter alia, for the treatment of CNS disorders, such as anxiety.

This application is a continuation of application Ser. No. 07/748,496,filed Aug. 22, 1991, now abandoned, which is a continuation-in-part ofU.S. patent application Ser. No. 07/511,150 filed 19 Apr. 1990 nowabandoned by Ian A. Cliffe and entitled "Piperazine Derivatives".

This invention relates to piperazine derivatives, to processes for theirpreparation, to their use and to pharmaceutical compositions containingthem. The novel compounds act: on the central nervous system by bindingto 5-HT receptors (as more fully explained below) and hence can be usedas medicaments for treating humans and other mammals.

The novel compounds of the invention are those of the general formula##STR2## and the pharmaceutically acceptable acid addition saltsthereof.

In formula (I)

n is one of the integers 1 or 2.

R is hydrogen or lower alkyl,

R¹ is an aryl or a monocyclic or bicyclic nitrogen containing heteroarylradical,

R² is hydrogen or lower alkyl,

R³ is an aryl radical, an alkyl radical containing 4 to 8 carbon atomsor an aryl(lower)alkyl radical,

X is --OCOR¹⁰, --CO₂ R⁶, --CONR⁵ R⁹, --OCO₂ R⁶, --NR⁴ COR⁶, OCONHR¹¹,--NHCO₂ R⁶, --NR⁴ CONHR⁶, --CONHNHR⁶, --CONHOR⁶, ##STR3##

R⁴ and R⁵ are each hydrogen or lower alkyl

R⁶ is --CHR⁷ R⁸, cycloalkyl of 3 to 12 carbon atoms or aryl(lower)alkyl(where R⁷ and R⁸ are each hydrogen or lower alkyl),

R⁹ is hydrogen, an alkyl group of 1 to 8 carbon atoms other than atertiary alkyl group, cycloalkyl of 3 to 12 carbon atoms,cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl or8-azaspiro[4.5]deca-7,9-dione-8-yl(lower)alkyl (lower)alkyl [with theproviso that when R³ is aryl or aralkyl, R⁹ is not a phenyl groupsubstituted in the ortho position by halogen, nitro, trifluoroalkyl,cyano, sulphonic acid, sulphonamido, carboxy, carbalkoxy,carboxylanilino or a 4-carboxylamino-benzosulphonamido group and thatwhen R⁹ is hydrogen, alkyl, aryl or aryl(lower)alkyl R⁵ is, hydrogen or--CHR⁷ R⁸ ],

or R⁵ and R⁹ together with the nitrogen atom to which they are attachedrepresent an azetidino, pyrrolidino, piperidino, hexahydroazepino,morpholino or piperazino ring which may be optionally substituted bylower alkyl, aryl or aryl(lower)alkyl

R¹⁰ is cycloalkyl of 3 to 12 carbon atoms, or2,3-dihydro[1,4]benzodioxinyl optionally substituted by lower alkyl,lower alkoxy or halogen or, when R3 is an alhyl radical containing 4 to8 carbon atoms, R¹⁰ can also be aryl;

R¹¹ is cycloalkyl of 3 to 12 carbon atoms, aryl or aryl(lower)alkyl,

R¹² and R¹³ are each lower alkyl or together with the carbon atom towhich they are both attached represent C₄₋₆ cycloalkyl,

R¹⁴ represents hydrogen, halogen, lower alkyl or lower alkoxy and

Y is CO or SO₂.

The term "lower" as used herein means that the radical referred tocontains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4carbon atoms. Examples of "lower alkyl" are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.-butyl, pentyl and isopentyl. When R³is an alkyl group of 4 to 8 carbon atoms it may be a straight orbranched chain group; a preferred example is tert.-butyl. Preferably R³is an aryl radical.

When used herein "aryl" means an aromatic radical having 6 to 12 carbonatoms (e.g. phenyl, naphthyl) which optionally may be substituted by oneor more substituents commonly used in medicinal chemistry, e.g.substituents such as lower alkoxy, halogen, trifluoromethyl, nitro,carbalkoxy, carboxamido, cyano, amino, (lower)alkylamino anddi(lower)alkylamino.

Examples of aryl(lower)alkyl and aryl(lower)alkoxy include, for example,benzyl and benzyloxy in which the phenyl group may be substituted asdefined above.

When used herein "nitrogen containing heteroaryl radical" means anaromatic ring containing one or more nitrogen atoms as heteroatoms (e.g.pyridinyl, pyrimidinyl or pyrazinyl) which may optionally be substitutedby one or more lower alkyl, lower alkoxy, halogen, trifluoromethyl,amino, (lower)alkylamino or di(lower)alkylamino substituents. When R¹ isa "nitrogen containing heteroaryl radical", it is a mono or bicyclicheteroaromatic radical containing 5 to 10 ring atoms, the heteroaromaticradical containing, as heteroatoms, one or two nitrogen atoms andoptionally a sulphur or oxygen atom, which is optionally substituted asjust described. Preferaby the heteroaryl radical is monocyclic.

Preferred compounds are:

those in which n is 1;

those in which R¹ is aryl particularly an optionally substituted phenylsuch as o-methoxyphenyl;

those in which R is hydrogen;

those in which R² is hydrogen;

those in which R³ is aryl particularly optionally substituted phenyl;

those in which X is an ester grouping of formula --CO₂ R⁶ or an amidegrouping of formula --CONR⁵ R⁹ particularly where --NR⁵ R⁹ represents acyclic grouping e.g. piperidino or hexahydroazepino.

The compounds of the invention may be prepared by a number of methodsknown in the art from known starting materials or starting materialsthat may be prepared by conventional methods. In one method forpreparing an amide of formula (I), where X represents --CONR⁵ R⁹ anamine of formula

    NHR.sup.5 R.sup.9                                          (II)

where R⁵ and R⁹ are as defined above is acylated with an acid of formula##STR4## (where R, R¹, R² and R³ and are as defined above) or with anacylating derivative thereof. Examples of acylating derivatives includethe acid halides (e.g. acid chlorides), azides, anhydrides, imidazolides(e.g. obtained from carbonyldiimidazole), activated esters or O-acylureas obtained from a carbodiimide such as a dialkylcarbodiimideparticularly dicyclohexylcarbodiimide. Preferably the amine is acylatedwith the acid in presence of a coupling agent such as1,1'-carbonyldiimidazole, iso-butylchloroformate or diphenylphosphinylchloride.

The acids of formula III are novel compounds and are also provided bythis invention.

The reverse amides, i.e. the compounds of the invention in which X is--NR⁴ COR⁶ may be prepared in an analogous manner to the amidesmentioned above by acylating the piperazine alkylamine ##STR5## with anacid of formula

    R.sup.6 COOH

or with an acylating derivative thereof.

Similarly, the compounds of the invention in which X is ##STR6## may beprepared by reacting an amine of formula ##STR7## with an anhydride offormula ##STR8## or with an acid of formula ##STR9##

An ester of the invention in which --X is --CO₂ R⁶ may be prepared byesterification of the acid of formula (III) above with an alcohol offormula R⁶ OH.

The reverse esters, i.e. the compounds in which X is --OCOR¹⁰, may beprepared by esterifying a piperazine alcohol of formula ##STR10## withan acid of formula R¹⁰ COOH.

Both types of esterification may be carried out, by methods known in theart. For example an acid halide may be reacted with the appropriatealcohol.

The ureas, i.e. compounds in which X is --NR⁴ CONHR⁶ and the carbamates,i.e. compounds in which X is --O.CO.NHR¹¹ may be prepared by reactingthe piperazinyl-alkanol or -alkylamine of formula ##STR11## with theappropriate isocyanate, The reverse carbamates, i.e. the compounds inwhich X is --NHCO₂ R⁶ may be prepared in a similar manner from thepiperazine isocyanate derivative ##STR12## and the alcohol R⁶ OH, or byreacting an amine of formula ##STR13## with a compound of formula R⁶OCOHal (where Hal is halogen, e.g. chlorine).

The hydroxylamine compounds of the invention, i.e. compounds in which Xis CONHOR⁶ may be prepared by reacting the acid of formula (III) abovewith a hydroxylamine of formula NH₂ OR⁶.

The hydrazide compounds of the invention, i.e. compounds in which X is--CONHNHR⁶ may be prepared by reacting the acid of formula (III) with ahydrazide of formula NH₂ NHR⁶.

An alternative method of preparing the compounds of the inventioncomprises alkylation of a piperazine of formula ##STR14## (where R andR¹ are as defined above) with an alkylating agent providing the group

    --(CH.sub.2).sub.n CR.sup.2 R.sup.3 X                      (V)

(where n, R², R³ and X are as defined above).

The alkylating agent may be, for example, a compound of formula

    Z--CH.sub.2 CR.sup.2 R.sup.3 X                             (VI)

where R², R³ and X are as defined above and Z is a leaving group such ashalogen or an alkyl- or aryl-sulphonyloxy group. Alternatively thealkylating agent may be an unsaturated compound of formula

    CH.sub.2 ═CR.sup.3 X                                   (VII)

(where R³ and X are as defined above) and the compound of formula (VII)is reacted with the piperazine of formula (IV) by means of a Michaelreaction. The reaction may be carried out at elevated temperature in thepresence of an alcohol. A small quantity of an acid catalyst may beemployed in the reaction when X represents --CONR⁵ R⁹.

The starting materials for the processes described above may be preparedby methods known in the art. For example certain acids of formula (III)may be prepared by Michael reaction of an acid of formula

    CH.sub.2 ═CR.sup.3 COOH                                (VIII)

and a piperazine of formula ##STR15## in a method similar to the Michaelreaction described above. The unsaturated compound of formula (VII) maybe prepared from the acid of formula (VIII) by the known methods ofobtaining amides and esters from acids. In a preferred method the acidis reacted with an amine in the presence of a condensing agent such asisobutylchloroformate or the acid is esterified, e.g. by reaction withan alcohol in presence of 2-chloro-1-methylpyridinium iodide. The acidsof formula (VIII) are known or may be prepared by methods known in theart.

The amides of formula (I) in which X is --CONR⁵ R⁹ where R⁵ is hydrogenand R⁹ is a secondary (lower)alkyl group may be prepared by analternative method comprising reacting a nitrile of formula ##STR16##with a secondary alcohol under acidic conditions as in the Ritterreaction. The nitrile (IX) may also be subjected to acid hydrolysis togive an amide of formula (I) in which X is CONH₂. Furthermore thenitrile may be hydrolysed to the acid (III) which may then be convertedto compounds of formula (I) by the methods given above. The nitrile offormula (IX) may be prepared by known methods such as reacting anunsaturated nitrile of formula CH₂ ═CR₃ CN with a piperazine of formula(IV) under Michael conditions or reacting a ketone of formula ##STR17##with p-toluenesulphonylisocyanide.

A further method of preparing the amides of formula in which X is--CONHR⁹ comprises the desulphurisation of a sulphur containing compoundof formula ##STR18## where R, R¹ and R⁹ are as defined above and R³ isaryl. The desulphurisation may be carried out in presence of a nickelcatalyst. The compound of formula (XI) may be prepared by a Willgerodtreaction, e.g. an aryl alkyl ketone of formula CH₃ CO.R³ is reacted withsulphur and a piperazine of formula (IV) and the resulting thioamide istreated with a base and with a isocyanate of formula R⁹ NCO.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Ifthe compound of the invention is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid additionsalt. Conversely, if the product of the process is a free base an acidaddition salt, particularly a pharmaceutically acceptable acid additionsalt, may be obtained by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

Examples of acid addition salts are those formed from inorganic andorganic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric,tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic,p-toluenesulphonic, oxalic and succinic acids.

The compounds of the invention may contain one or more asymmetric carbonatoms, so that the compounds can exist in different steroisomeric forms.The compounds can be for example, racemates or optically active forms.The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis.

The compounds of the present invention possess pharmacological activity.In particular, they act on the central nervous system by binding to 5-HTreceptors. In pharmacological testing it has been shown that thecompounds particularly bind to receptors of the 5-HT_(1A) type. Ingeneral, the compounds selectively bind to receptors of the 5-HT_(1A)type to a much greater extent than they bind to other receptors such asα₁ and D₂ receptors. Many exhibit activity as 5-HT_(1A) antagonists inpharmacological testing. The pharmacological testing of the compoundsindicates that they can be used for the treatment of CNS disorders, suchas anxiety in mammals, particularly humans. They may also be useful asantidepressants, hypotensives and as agents for regulating thesleep/wake cycle, feeding behaviour and/or sexual function.

The compounds of the invention were tested for 5-HT_(1A) receptorbinding activity in rat hippocampal membrane homogenate by the method ofB. S. Alexander and M. D. Wood, J Pharm Pharmarol, 1988, 40, 888-891.The results for representative compounds of the invention are givenbelow.

    ______________________________________                                        Compounds of Example                                                                             IC.sub.50 (nM)                                             ______________________________________                                         6                 127                                                         8                 45                                                         19                 24                                                         21                 49                                                         22                 45                                                         23                 59                                                         24                 75                                                         26                 46                                                         29                 25                                                         31                 28                                                         32                 21                                                         33                 8                                                          34                 9                                                          35                 16.5                                                       37                 45                                                         39                 22                                                         40                 78                                                         42                 88                                                         43                 37                                                         59                 1                                                          ______________________________________                                    

The affinity for D₂ receptor sites C as measured by the procedure of A.A. Hancock et al, Mol Pharmacol, 1984, 26, 439) and for α₁ sites (asmeasured by the procedure of A. L. Morrow et al, Mol Pharmacol, 1986,29, 321) for various compounds is given below:

    ______________________________________                                                       Affinity for                                                                            Affinity for                                         Compound of    D.sub.2 site                                                                            α.sub.1 site                                   Example        IC.sub.50 (nM)                                                                          IC.sub.50 (nM)                                       ______________________________________                                        19               6290     976                                                 21                       1200                                                 22                       1230                                                 24                       .sup. >10.sup.4                                      26                       1090                                                 29                       1140                                                 32             >10000     851                                                 37                       7310                                                 42                       2850                                                 43                        988                                                 ______________________________________                                    

The compounds are tested for 5-HT_(1A) receptor antagonism activity in atest involving the antagonism of 5-carboxamidotryptamine in theguine-pig ileum in in vitro (based upon the procedure of Fozard et al,Br J Pharmac, 1985, 86, 601P). The results for compounds of theinvention are given below.

    ______________________________________                                        Compound of Example                                                                              pA.sub.2                                                   ______________________________________                                        19                 6.9                                                        21                 6.9                                                        23                 7.0                                                        26                 6.8                                                        31                 7.4                                                        32                 6.8                                                        37                 7.6                                                        43                 6.9                                                        59                 9.0                                                        ______________________________________                                    

The invention also provides a pharmaceutical composition comprising acompound or a pharmaceutically acceptable acid addition salt thereof inassociation with a pharmaceutically acceptable carrier. Any suitablecarrier known in the art can be used to prepare the pharmaceuticalcomposition. In such a composition, the carrier is generally a solid orliquid or a mixture of a solid or liquid.

Solid form compositions include powders, granules, tablets, capsules(e.g. hard and soft gelatine capsules), suppositories and pessaries. Asolid carrier can be, for example, one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,fillers, glidants, compression aides, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders the carrieris a finely divided solid which is in admixture with the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably1 to 80% of the active ingredient. Suitable solid carriers include, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose,dextrin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

The term "composition" is intended to include the formulation of anactive ingredient with encapsulating material as carrier to give acapsule in which the active ingredient (with or without other carriers)is surrounded by the carrier, which is thus in association with it.Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions,emulsions, syrups, elixirs and pressurised compositions. The activeingredient, for example, can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilisers, emulsifiers, buffers, preservatives, sweeteners,flavouring agents, suspending agents, thickening agents, colours,viscosity regulators, stabilisers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g. cellulose derivatives,preferably sodium carboxymethyl cellulose solution), alcohols, e.g.glycerol and glycols) and their derivatives, and oils (e.g. fractionatedcoconut oil and arachis oil). For parenteral administration the carriercan also be an oily ester such as ethyl oleate and isopropyl myristate.Sterile liquid carriers are used in sterile liquid form compositions forparenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. When the compound is orally active it can beadministered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged composition, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquid. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form. The quantity of the active ingredient in unit dose ofcomposition may be varied or adjusted from 0.5 mg or less to 750 mg ormore, according to the particular need and the activity of the activeingredient.

The following Examples illustrate the invention:

EXAMPLE 1 α-{1-[4-(2-Methoxyphenyl)piperazinyl]methyl}benzeneacetic acid

1-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours,cooled to room temperature, and evaporated in vacuo. The solid wastriturated with acetone (3×100 ml) to give a first crop of product (13.8g) as white crystals. The filtrate was evaporated in vacuo to give anoil which slowly crystallised over 1 month. The solid was trituratedwith acetone (200 ml) to give a second crop of the hemihydrate of theproduct (9.01 g) as white crystals, m.p. 160°-163°.

(Found: C, 68.4; H, 7.2; N, 7.9. C₂₀ H₂₄ N₂ O₃.0.5H₂ O requires C, 68.8;H, 7.2; N, 8.0%.)

EXAMPLE 22-{1-[4-(2-Methoxyphenyl)piperazinyl]methyl}-3-benzenepropanoic acid

2-(Phenylmethyl)propenoic acid (Mannich and Ganz, Chem. Ber., 1922, 55,3486) (2.00 g, 12.35 mmol) and 1-(2-methoxyphenyl)piperazine (2.37 g,12.35 mmol) in propanol (25 ml) were heated under reflux for 18 hours,cooled to room temperature, and evaporated in vacuo. The residue wastriturated with acetone and ether to give the product (0.80 g) as acolourless powder, m.p. 155°-158°.

(Found: C, 71.6; H, 7.4; N, 7.6. C₂₁ H₂₆ N₂ O₃ requires C, 71.2; H, 7.3;N, 7.9%.)

EXAMPLE 3 2-Phenyl-N-(phenylmethyl)propenamide

A stirred solution of atropic acid (10.3 g, 69.5 mmol) in drytetrahydrofuran (100 ml) was treated under nitrogen withN-methylmorpholine (7.7 ml, 70.0 mmol), cooled to -10°, treated dropwisewith iso-butylchloroformate (9 ml, 69.4 mmol), treated dropwise withbenzylamine (7.6 ml, 69.6 mmol), warmed to room temperature over 1 hour,filtered and evaporated in vacuo to give a yellow oil which wasdissolved in ether (100 ml). The solution was washed with 0.1N-HCl (200ml), brine (100 ml), 0.1N-NaOH (100 ml) and brine (100 ml), dried(MgSO₄), and evaporated in vacuo to give a yellow liquid. Purificationby chromatography (silica; di-iso-propyl ether) gave the product aswhite crystals (7.3 g), m.p. 84°-86° (from di-iso-propyl ether).

(Found: C, 80.8; H, 6.3; N, 5.7. C₁₆ H₁₅ NO requires C, 81.0; H, 6.4; N,5.9%.)

EXAMPLE 4 N-Cyclohexyl-2-phenylpropenamide

This compound was made from atropic acid (10.48 g, 70.8 mmol),N-methylmorpholine (7.8 ml, 70.9 mmol), iso-butyl chloroformate (9.2 ml,70.9 mmol), and cyclohexylamine (8.1 ml, 70.7 mmol) using the proceduredescribed in Example 3. The crude product was purified byrecrystallisation from cyclohexane to give the product (4.69 g), aswhite crystals, m.p. 131°-133°.

Found: C, 78.7; H, 8.8; N, 5.95. C₁₅ H₁₉ NO requires C, 78.6; H, 8.35;N, 6.1%.)

EXAMPLE 5 Propyl3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanoate

A stirred solution of atropic acid (2.11 g, 14.3 mmol) and cyclohexanol(1.51 ml, 14.2 mmol) in ethyl acetate (40 ml) at 2°-5° was treateddropwise with N,N'-dicylohexylcarbodiimide (3.27 g, 15.8 mmol), warmedto room temperature, filtered and evaporated in vacuo to give a yellowoil.

A solution of the oil in propanol (20 ml) was heated under reflux for 1day, cooled to room temperature, evaporated in vacuo, and the residuepurified by chromatography [silica; ether-hexane (1:3) and silica;di-iso-propyl ether] to give the free base as an oil (1.1 g).

Formation of the salt in the usual manner gave the hydrochloride (0.95g), m.p. 200°-204°.

(Found: C, 60.9; H, 7.25; N, 6.3. C₂₃ H₃₀ N₂ O₃.2HCl requires C, 60.7;H, 7.1; N, 6.15%.)

EXAMPLE 63-{1-[4-(2-Methoxyphenyl)piperazinyl]}-2-phenyl-N-phenylpropanamide

A solution of the product of Example 1 (1.102 g, 3.2 mmol) indichloromethane (50 ml) was treated with 1,1'-carbonyldiimidazole (0.58g, 3.6 mmol), stirred for 1 hour, treated with aniline (0.4 ml, 4.4mmol), stirred for 18 h, evaporated in vacuo, and the residue purifiedby chromatography (silica; di-iso-propyl ether→ether). The foam wasdissolved in hot propan-2-ol (10 ml) and the solution acidified withethereal hydrogen chloride. Evaporation in vacuo gave a glass whichcrystallised upon trituration with ether as the dihydrochloride quarterhydrate salt of the product (0.897 g), m.p. 250°-255° (dec.).

Found: C, 63.4; H, 6.8; N, 8.5. C₂₆ H₂₉ N₃ O₂.2HCl1/4H₂ O requires C,63.35; H, 6.4; N, 8.5%.)

EXAMPLES 7-21

The following 3-{1-[4-(2-methoxyphenyl)piperazinyl]}2-phenylpropanamideswere prepared following the procedure of Example 6 but using theindicated amine reactant instead of aniline.

    __________________________________________________________________________    3-{1-4-(2-Methoxyphenyl)piperazinyl]}-2-phenylpropanamides                                                      Found %                                          Amine   Amide                (Required) m.p.                             Example                                                                            Reactant                                                                              Product  Formula     C   H  N   (°C.)                     __________________________________________________________________________     7   NH.sub.3 -THF                                                                         amide    C.sub.20 H.sub.25 N.sub.3 O.sub.2 2HCl                                                    58.05                                                                             6.7                                                                              10.2                                                                              194-195                                                            (58.25)                                                                           (6.6)                                                                            (10.2)                                8   MeNH.sub.2 -EtOH                                                                      methylamide                                                                            C.sub.21 H.sub.27 N.sub.3 O.sub.2 2HCl3/4H.sub.2                                          57.6                                                                              7.15                                                                             9.2 203-205                               (33% W/W)                    (57.3)                                                                            (7.0)                                                                            (9.55)                                9   EtNH.sub.2 -EtOH                                                                      ethylamide                                                                             C.sub.22 H.sub.29 N.sub.3 O.sub.2 2HCl1/4H.sub.2                                          59.4                                                                              7.2                                                                              9.5 204-206                               (33% W/W)                    (59.4)                                                                            (7.1)                                                                            (9.4)                                10   PrNH.sub.2                                                                            propylamide                                                                            C.sub.23 H.sub.31 N.sub.3 O.sub.2 2HCl                                                    60.6                                                                              7.6                                                                              9.7 213-215                                                            (60.8)                                                                            (7.3)                                                                            (9.25)                               11   BuNH.sub.2                                                                            butylamide                                                                             C.sub.24 H.sub.33 N.sub.3 O.sub.2 2HCl                                                    61.6                                                                              7.8                                                                              9.2 199-200                                                            (61.5)                                                                            (7.5)                                                                            (9.0)                                12   iso-PrNH.sub.2                                                                        iso-propylamide                                                                        C.sub.23 H.sub. 31 N.sub.3 O.sub.2 2HCl                                                   60.55                                                                             7.6                                                                              9.6 221-224                                                            (60.8)                                                                            (7.3)                                                                            (9.25)                               13   iso-BuNH.sub.2                                                                        iso-butylamide                                                                         C.sub.24 H.sub.33 N.sub.3 O.sub.2 2HCl                                                    61.4                                                                              7.7                                                                              9.0 202-203                                                            (61.5)                                                                            (7.5)                                                                            (9.0)                                14   C.sub.3 H.sub.5 CH.sub.2 NH.sub.2                                                     cyclopropyl-                                                                           C.sub.24 H.sub.31 N.sub.3 O.sub.2 2HCl                                                    61.9                                                                              7.0                                                                              8.7 200-202                                       methylamide          (61.8)                                                                            (7.1)                                                                            (9.0)                                15   .sub.- t-BuCH.sub.2 NH.sub.2                                                          neopentylamide                                                                         C.sub.25 H.sub.35 N.sub.3 O.sub.2 2HCl                                                    61.9                                                                              7.6                                                                              8.7 200-203                                                            (62.2)                                                                            (7.7)                                                                            (8.7)                                16   C.sub.6 H.sub.13 NH.sub.2                                                             hexylamide                                                                             C.sub.26 H.sub.37 N.sub.3 O.sub.2 2HCl                                                    62.5                                                                              7.9                                                                              8.4 189-190                                                            (62.9)                                                                            (7.5)                                                                            (8.5)                                17   C.sub.6 H.sub.11 CH.sub.2 NH.sub.2                                                    cyclohexyl-                                                                            C.sub.27 H.sub.37 N.sub.3 O.sub.2 2HCl                                                    63.5                                                                              8.0                                                                              8.4 205-207                                       methylamide          (63.8)                                                                            (7.7)                                                                            (8.3)                                18   C.sub.5 H.sub.9 NH.sub.2                                                              cyclopentylamide                                                                       C.sub.25 H.sub.33 N.sub.3 O.sub.2 2HCl1/4H.sub.2                                          62.0                                                                              7.3                                                                              8.9 213-214                                                            (62.0)                                                                            (7.4)                                                                            (8.7)                                19   C.sub.6 H.sub.11 NH.sub.2                                                             cyclohexylamide                                                                        C.sub.26 H.sub.35 N.sub.3 O.sub.2 2HCl                                                    63.0                                                                              7.8                                                                              8.1 216-219                                                            (63.15)                                                                           (7.5)                                                                            (8.5)                                20   C.sub.7 H.sub.13 NH.sub.2                                                             cycloheptylamide                                                                       C.sub.27 H.sub.37 N.sub.3 O.sub.2 2HCl                                                    63.6                                                                              7.9                                                                              8.0 206-208                                                            (63.8)                                                                            (7.7)                                                                            (8.3)                                21   C.sub.11 H.sub.18 N.sub.2 O.sub.2.sup.a                                               .sup.b   C.sub.31 H.sub.40 N.sub.4 O.sub.4 2HCl                                                    61.4                                                                              7.3                                                                              9.2 148-152                                                            (61.5)                                                                            (7.0)                                                                            (9.25)                               __________________________________________________________________________     .sup.a 8(Aminoethyl)-8-azaspiro[4.5]deca7,9-dione                             .sup.b The product was                                                        8{{1[4(2-methoxyphenyl)piperazinyl]methyl}phenylacetamidoethyl8-azaspiro[    .5]deca7,9-dione                                                          

EXAMPLE 22 N,N-Dimethyl-3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanamide

A stirred solution of the product of Example 1 (1.786 g, 5.2 mmol) andN-methylmorpholine (0.65 ml, 5.9 mmol) in dichloromethane (20 ml) at-30° was treated with diphenylphosphinyl chloride (1.1 ml, 5.8 mmol)under an atmosphere of nitrogen. After 1 hour, 25-30% w/v dimethylaminein water (1.2 ml, ca. 7.5 mmol) was added and the solution warmed toroom temperature over 3 hours. Evaporation in vacuo and chromatography(silica, ethyl acetate) gave the free base (0.532 g.).

The solid was dissolved in hot methanol (5 ml) and the solutionacidified with ethereal hydrogen chloride and evaporated in vacuo togive the dihydrochloride three-quarter hydrate salt of the product(0.581 g) as colourless crystals, mp. 236°-238° (dec.).

Found: C, 58.1; H, 7.41; N, 9.1. C₂₂ H₂₉ N₃ O₂.2HCl.3/4H₂ O requires C,58.2; H, 7.2; N, 9.3%.)

EXAMPLE 233-{1-[4-(2-Methoxyphenyl)piperazinyl]}-2-phenyl-N-(phenylmethyl)propanamide

A solution of the product of Example 3 (1.25 g, 5.3 mmol),1-(2-methoxyphenyl)piperazine (1.00 g, 5.2 mmol), and acetic acid (3drops) was heated under reflux under an atmosphere of nitrogen for 40hours, cooled to room temperature, and evaporated in vacuo to give anoil which crystallised from ethyl acetate. A suspension of the crystalsin hot propan-2-ol was acidified with ethereal hydrogen chloride. Thehot solution was cooled to room temperature and the precipitate filteredand washed with propan-2-ol and ether to give the product (1.94 g), m.p.211°-214°.

(Found: C, 64.5; H, 7.1; N, 7.9. C₂₇ H₃₁ N₃ O₂.2HCl requires C, 64.5; H,6.6; N, 8.4%.)

EXAMPLE 24N-Cyclohexyl-2-phenyl-3-{1-[4-(2-pyrimidinyl)piperazinyl]}propanamide

A solution of the product of Example 4 (0.90 g, 3.9 mmol) andN-(2-pyrimidyl)piperazine dihydrochloride (0.95 g, 4.0 mmol) in 1N-NaOH(8.0 ml), propanol (10 ml), and acetic acid (8 drops) was heated underreflux for 48 hours, cooled to room temperature, and concentrated invacuo. The aqueous residue was diluted with water (50 ml) and extractedwith dichloromethane (50 ml). The extracts were washed with water (50ml), dried (MgSO₄), and evaporated in vacuo to give an oil. Purificationby column chromatography (alumina; ether) gave the product free base(0.63 g) as colourless crystals.

The crystals were dissolved in hot propan-2-ol (20 ml), acidified withethereal hydrogen chloride, and evaporated in vacuo to give a foam whichcrystallised upon trituration with ether as the dihydrochloridethree-quarter hydrate salt of the product (0.67 g) m.p. 165°-175°.

(Found: C, 62.5; H, 7.6; N, 15.6. C₂₃ H₃₁ N₅ O.HCl.3/4H₂ O requires C,62.3; H, 7.6; N, 15.8%.)

EXAMPLE 253,N-Bis{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanamide

This compound was isolated as a side-product from the reaction followingthe procedure of Example 6 but substituting t-butylamine for aniline.The dihydrochloride trihydrate of the product was produced by standardmethods as colourless crystals, m.p. 180°-190° (dec.)

(Found: C, 57.9; H, 7.3; N, 8.3. C₃₁ H₃₈ N₄ O₃.2HCl.3H₂ O requires C,58.0; H, 7.2; N, 8.7%.)

EXAMPLE 26 2-Methylpropyl3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanoate Step 1:2-Methylpropyl 2-phenylpropenoate

This compound was isolated as a side-product from the reaction describedin Example 3 as a colourless oil (1.03 g) and was used without furtherpurification in Step 2.

Step 2: 2-Methylpropyl3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanoate

A solution of the product of Step 1 (0.97 g, 4.7 mmol) and1-(2-methoxyphenyl)piperazine (0.91 g, 4.7 mmol) in propanol (10 ml) wasmaintained at room temperature for 90 hours and evaporated in vacuo. Theresidue was purified by chromatography (silica; di-iso-propyl ether) togive an oil. The oil was dissolved in propan-2-ol (10 ml) and thesolution acidified with ethereal hydrogen chloride and evaporated invacuo. The solid was triturated with ether to give the dihydrochloridesalt of the product (1.173 g) m.p. 208°-212°.

(Found: C, 61.6; H 7.6; N, 5.8. C₂₄ H₃₂ N₂ O₃ 2HCl requires C, 61.4; H,7.3; N, 6.0%.)

EXAMPLE 27 Ethyl3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanoate

This compound was isolated as a side-product from the reaction describedin Example 9. The dihydrochloride salt of the product, mp. 220°-222° wasproduced in the conventional manner.

(Found: C, 59.5; H, 6.9; N, 6.5. C₂₂ H₂₈ N₂ O₃ 2HCl requires C, 59.9; H,6.85; N, 6.35%).

EXAMPLE 282-{1-[4-(2-Methoxyphenyl)piperazinyl]methyl}-N-methyl-3-phenypropanamide

This compound was prepared from the acid of Example 2 (2.00 g, 5.65mmol) 1,1'-carbonyldiimidazole (0.92 g, 5.65 mmol), and methylaminesolution, approx 33% w/w in industrial methylated spirit (0.58 g, ca 6.2mmol) using the processes outlined in Example 6. The hydrochloridehydrate salt of the product was isolated as crystals (0.73 g), m.p.186.5°-188.5° (from methyl acetate-ether).

(Found: C, 62.8; H, 7.6; N, 10.0. C₂₂ H₂₉ N₃ O₂.HCl.H₂ O requires C,62.6; H, 7.9; N, 10.0%.)

EXAMPLE 29 Ethyl2-}1-[4-(2-methoxyphenyl)piperazinyl]methyl}-3-phenylpropanoate

This compound was prepared from the acid of Example 2 (2.00 g, 5.65mmol) by a method analogous to that described in Example 28 with theexception that excess ethanol was used in place of methylamine. Thedihydrochloride quarter hydrate salt of the salt (1.20 g) was isolatedas crystals, m.p. 197°-201°.

(Found: C, 60.2; H, 7.3; N, 6.0. C₂₃ H₃₀ N₂ O₃.2HCl.1/4H₂ O requires C,60.1; H, 7.1; N, 6.1%.)

EXAMPLES 3-36

The following3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropanamides wereprepared following the procedure of Example 6, but using the indicatedamine reactant instead of aniline.

    __________________________________________________________________________    3-{1-[4-(2-Methoxyphenyl)piperazinyl]}-2-phenylpropanamides                                                   Found %                                            Amine   Amide              (Required) m.p.                               Example                                                                            Reactant                                                                              Product Formula    C   H  N   (°C.)                       __________________________________________________________________________    30   3,3-dimethyl-                                                                         (3,3-dimethyl)-                                                                       C.sub.26 H.sub.37 N.sub.3 O.sub.2.2HCl                                                   62.6                                                                              8.0                                                                              8.5 187-193                                 butylamine                                                                            butylamide         (62.9)                                                                            (7.9)                                                                            (8.5)                                  31   cyclopropyl-                                                                          cyclopropyl-                                                                          C.sub.23 H.sub.29 N.sub.3 O.sub.2.2HCl                                                   60.7                                                                              7.2                                                                              9.2 193-195                                 amine   amide              (60.5)                                                                            (7.0)                                                                            (9.2)                                  32   pyrrolidine                                                                           .sup.c  C.sub.24 H.sub.31 N.sub.3 O.sub.2.2HCl.                                                  61.4                                                                              7.4                                                                              9.0 212-213                                                 0.25H.sub.2 O                                                                            (61.3)                                                                            (7.2)                                                                            (8.9)                                  33   piperidine                                                                            .sup.d  C.sub.25 H.sub.33 N.sub.3 O.sub.2.1.75HCl                                                63.7                                                                              7.5                                                                              8.8 191-194                                                            (63.7)                                                                            (7.4)                                                                            (8.9)                                  34   hexamethylene-                                                                        .sup.e  C.sub.26 H.sub.35 N.sub.3 O.sub.2.1.5HCl                                                 65.75                                                                             7.9                                                                              8.8 203-204                                 imine                      (65.6)                                                                            (7.9)                                                                            (8.8)                                  35   cyclooctyl-                                                                           cyclooctylamide                                                                       C.sub.28 H.sub.39 N.sub.3 O.sub.2.2HCl                                                   64.3                                                                              7.9                                                                              8.0 204-206                                 amine                      (64.3)                                                                            (7.9)                                                                            (8.0)                                  36   cyclododecyl-                                                                         cyclododecyl-                                                                         C.sub.32 H.sub.47 N.sub.3 O.sub.2.2HCl.                                                  66.0                                                                              8.5                                                                              7.2 184-188                                 amine   amide   0.25H.sub.2 O                                                                            (65.9)                                                                            (8.6)                                                                            (7.2)                                  __________________________________________________________________________     .sup.c 1{3{1[4(2-methoxyphenyl)piperazinyl]2-phenylpropionyl}pyrrolidine      .sup.d 1{3{1[4(2-methoxyphenyl)piperazinyl]2-phenylpropionyl}piperidine       .sup.e                                                                        2,3,4,5,6,7hexahydro-1-{3{1[4(2-methoxyphenyl)piperazinyl]2-phenylpropion    l1H-azepine                                                               

EXAMPLE 37(S)-N-[2-[1-[4-(2-Methoxyphenyl)piperazinyl]]-1-phenylethyl]cyclohexanecarboxylicacid amide

A solution of(S)-2-{1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethylamine (1.03 g,3.3 mmol) in dichloromethane (50 ml) was treated withcyclohexanecarboxylic acid chloride (0.5 ml, 3.7 mmol), after 40 minuteswashed with 0.1N-NaOH (100 ml), dried (MgSO₄), evaporated in vacuo, andthe residual oil purified by column chromatography [silica; di-isopropylether→ether] to give the product free base (0.83 g) as white crystals.

The crystals were dissolved in hot propan-2-ol, acidified with etherealhydrogen chloride, evaporated in vacuo, and the resulting pink crystalsdried in vacuo at 70° for 24 hours to give the title compound as thehydrochloride hydrate, m.p. 141°-143°.

(Found: C, 65.7; H, 8.0; N, 9.2. C₂₆ H₃₅ N₃ O₂.HCl.H₂ O requires C,65.6; H, 8.05; N, 8.8%.)

EXAMPLE 38O-[2-[1-(4-(2-Methoxyphenyl)piperazinyl)]-1-phenylethyl]-N-cyclohexylcarbamate

Tributyltin methoxide (0.05 ml) was added to a solution of2-[1-(4-(2-methoxyphenyl)piperazinyl)]-1-phenylethanol (1.00 g, 3.2mmol) and cyclohexylisocyanate (0.44 g, 3.5 mmol) in dry toluene (10.0ml). The reaction mixture was stirred at room temperature overnight andthe suspension was treated with dichloromethane to afford a solutionwhich was chromatographed on silica gel, gradient eluting with hexaneethyl acetate (2:1 to 1:2) to afford a white solid. The solid wasdissolved in ethyl acetate and the solution acidifed with etherealhydrogen chloride to afford the title compound as the dihydrochloridesemihydrate (1.3 g), m.p. 182.4°-186.3°.

(Found: C, 60.4; H, 7.2; N, 8.0. C₂₆ H₃₅ N₃ O₃.2HCl.1/2H₂ O requires C,60.1; H, 7.4; N, 8.1%.)

EXAMPLE 39O-[2-[1-[4-(2-Methoxyphenyl)piperazinyl]]-1-phenylethyl]-N-phenylcarbamate

The above compound was prepared following the procedure of Example 38but substituting phenylisocyanate for cyclohexylisocyanate. The productwas obtained as the dihydrochloride, m.p. 189.4°-191.7°.

EXAMPLE 40 2-{1-[4-(2-Methoxyphenyl)piperazinyl]}-1-phenylethylcyclohexanecarboxylate

2-[1-(4-(2-Methoxyphenyl)piperazinyl)]-1-phenyl ethanol dihydrochloride(1.50 g, 3.9 mmol) was treated with cyclohexanecarbonyl chlorideprepared from the corresponding acid (1.0 g, 7.8 mmol) by reaction withthionyl chloride in chloroform and diisopropylethylamine (2.26 g, 17.5mmol) in chloroform (15 ml). The crude product was chromatographed andthe oil obtained was dissolved in acetonitrile and acidified withethereal hydrogen chloride to afford the title compound as thedihydrochloride, m.p. 213.2°-217.4°.

(Found: C, b 63.0; H, 7.3; N, 5.6. C₂₆ H₃₄ N₂ O₃.2HCl requires C, 63.0;H, 7.3; N, 5.7%.)

EXAMPLE 41(S)-1-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]-1-phenylethyl]-3-phenylurea

Phenyl isocyanate (0.45 ml, 4.2 mmol) was added to(S)-2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethylamine in drytetrahydrofuran (10 ml) at 0° under an atmosphere of nitrogen. Thesolution was warmed to room temperature and after 18 hours evaporated invacuo. The residue was chromatographed (silica; ether), dissolved inmethanol, acidified with ethereal hydrogen chloride, and evaporated invacuo to give a foam. Crystallisation from ethyl acetate propan-2-olgave the product as the hydrochloride (0.572 g), m.p. 165°-170° (dec.).

(Found: C, 63.8; H, 7.0; N, 11.1. C₂₆ H₃₀ N₄ O₂.15/8HCl requires C,63.8; H, 6.5; N, 11.4%.)

EXAMPLE 42 Ethyl(S)-N-[2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethyl]carbamate

(S)-2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethylamine (0.94 g,3.0 mmol) in dichloromethane (20 ml) was treated with ethylchloroformate (0.4 ml, 4.2 mmol), and after 4 days evaporated in vacuo.The residue was chromatographed, dissolved in ethanol, acidified withconstant boiling hydrobromic acid, and evaporated in vacuo to give anoil. Crystallisation from ethyl acetate-propan-2-ol gave the product asthe dihydrobromide (0.08 g), m.p. 170°-180° (dec.).

(Found: C, 48.6; H, 6.01; N, 7.4. C₂₂ H₂₉ N₃ O₃.2HBr requires C, 48.5;H, 5.7; N, 7.7%.)

EXAMPLE 43 Methyl3-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylpropionate

1,1'-Carbonyldiimidazole (1.62 g, 10.0 mmol) was added to a stirredsuspension of 3-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylpropionicacid (3.40 g, 10.0 mmol) in dry tetrahydrofuran (40 ml). The mixture wasstirred at room temperature for 1 hour and methanol (40 ml, 32 g, 990mmol) was added. The solution was stirred at room temperature for 18hours, and was concentrated in vacuo to give a pale yellow oil. Theproduct was chromatographed on silica with eluant ether to give thetitle compound as the free base (2.37 g). A portion of the product (0.65g) was dissolved ethyl acetate (30 ml) and the solution was acidifiedwith ethereal hydrogen chloride (5 ml). The mixture was concentrated invacuo, the product was dissolved in methanol, and the solution wasconcentrated in vacuo. The product was triturated with acetonitrile togive the title compound as the dihydrochloride (691 mg), m.p. 211°-212°.

(Found: C, 58.8; H, 6.9; N, 6.3. C₂₁ H₂₆ N₂ O₃.2HCl requires C, 59.0; H,6.6; N, 6.5%.)

EXAMPLE 44N-(1-Ethylpropyl)-3-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylpropionamide

1,1'-Carbonyldiimidazole (649 mg, 4.0 mmol) was added to a stirredsuspension of 3-[1-[4-(2-methoxyphenyl]piperazinyl]]-2-phenylpropionicacid (1.36 g, 4.0 mmol) in dry tetrahydrofuran (20 ml). The mixture wasstirred at room temperature for 1 hour, and 1-ethylpropylamine (0.6 ml,0.45 g, 5.1 mmol) was added dropwise. The mixture was stirred at roomtemperature for 18 hours, and was concentrated in vacuo to give a whitesemi solid. The product was chromatographed on silica with eluant ethylacetate to give the title compound as the free base (0.90 g). Theproduct was dissolved in ethyl acetate (45 ml), and the solution wasacidified to give the dihydrochloride half hydrate (0.90 g), m.p.204°-208°.

(Found: C, 61.3; H, 7.8; N, 8.5. C₂₅ H₃₅ N₃ O₂.2HCl.O.5H₂ O requires C,61.1; H, 7.8; N, 8.55%.)

EXAMPLE 454-[3-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylpropionyl]morpholine

The above compound was prepared following the procedure of Example 44substituting morpholine for 1-ethylpropylamine. The product was isolatedas the dihydrochloride, m.p. 213°-217°.

EXAMPLE 461-{3-{1-[4-(2-Methoxyphenyl)piperazinyl]}-2-phenylpropionyl}azetidine

1,1-carbonyldiimidazole (0.81 g, 5 mmol) was added to a stirredsuspension of 3-{1-[4-(2-methoxyphenyl)piperazinyl]}-2-phenylpropionicacid (1.70 g, 5 mmol) in dry tetrahydrofuran (25 ml). The suspension wasstirred at room temperature for 1 h, and azetidine (1.12 g, 20 mmol) wasadded in one portion.

After 21 h the solution was concentrated in vacuo to give a solid whichwas purified by chromatography (silica; ethyl acetate). The free basewas dissolved in methanol, the solution was acidified with etherealhydrogen chloride and evaporated in vacuo, and the solid triturated withacetonitrile to give the product as the dihydrochloride quarter hydrate(0.25 g), m.p.: 181°-184° (Found: C, 60.4; H, 7.0; N, 9.3; C₂₃ H₂₉ N₃O₂.2HCl.0.25H₂ O requires C, 60.3; H, 6.9; N, 9.2%).

EXAMPLE 47 O-{2-[1-[4-(2-Methoxyphenyl)piperazinyl]]-1-phenylethyl}-N-(3-chlorophenyl)carbamate

Tributyltin methoxide (0.10 ml) was added to a stirred solution of2-{1-[4-(2-methoxyphenyl)piperazinyl]}-1-phenylethanol (1.60 g, 5.1mmol) and 3-chlorophenylisocyanate (0.87 g, 5.7 mmol) in dichloromethane(15 ml). The mixture was stirred for 70 h, filtered, and the filtrateevaporated in vacuo. The residue was purified by chromatography [silica;hexane-ethyl acetate (1:1→1:2] to afford an oil which solidified onstanding. The off white solid was dissolved in acetonitrile (10 ml) andacidified with ethereal hydrogen chloride to afford the product as theone and eight-tenth hydrochloride salt (1.57 g), m.p. 159.2°-163.0°(Found: C, 58.6; H, 5.9; N, 7.9; C₂₆ H₂₈ N₃ O₃ Cl.1.8HCl requires C,58.5; H, 5.6; N, 7.9%

EXAMPLE 481-Ethyl-3-{2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethyl}carbonate

Ethyl chloroformate (0.60 g, 5.5 mmol) was added to a solution of2-{1-[4-(2-methoxyphenyl)piperazinyl]}-1-phenylethanol 1.57 g, 5.0 mmol)and triethylamine (0.56 g, 5.5 mmol) in dichloromethane (15 ml). Themixture was stirred for 70 h, evaporated in vacuo, and the residuepurified by chromatography [silica; hexane-ethyl acetate (1:1)] toafford an oil. The oil was dissolved ina acetonitrile (10 ml) andacidified with ethereal hydrogen chloride to afford the dihydrochloridesalt of the product (0.41 g), m.p. 213°-215° (dec.) Found C, 57.6; H,6.7; N. 6.1; C₂₂ H₂₈ N₂ O₄.2HCl requires C, 57.8; H, 6.6; N, 6.1%)

EXAMPLE 49 2-{1-[4-(2-Methoxyphenyl)piperazinyl]}-1-phenylethylbenzo-2,4-dioxin-2-ylcarboxylate

Benzo-2,4-dioxin-2-ylcarboxylic acid (2.10 g, 11.7 mmol) in thionylchloride (10.0 ml) was heated under reflux for 1 h and the excessthionyl chloride removed under reduced pressure. The crude acid chloridewas dissolved in dichloromethane (10.0 ml) and a solution of2-{1-[4-(2-methoxyphenyl)piperazinyl]}-1-phenylethanol dihydrochloride(1.50 g, 3.9 mmol) in dichloro-methane (5.0 ml) added, followed bytriethylamine (1.22 g, 12.1 mmol). The mixture was stirred for 18 h,filtered and the filtrate evaporated in vacuo. The oil was purified bychromatography [silica; hexane-ethyl acetate (2:1→2;3], dissolved inacetonitrile (10 ml) and acidified with ethereal hydrogen to give theproduct as a dihydrochloride salt (1.37 g), m.p. 202°-206° (Found C,61.5; H, 6.0; N, 5.1 .C₂₈ H₃₀ N₂ O₅.2HCl requires C, 61.4; H, 5,9; 5.1%)

EXAMPLE 50 (S)-8-{2-[1-[4-(2-Methoxyphenyl)piperazinyl]]-1-phenylethyl}-8-azaspiro[4.5]decan-7,9-dione

A solution of (S)-2-{1-[4-(2-methoxyphenyl)piperazinyl]}-1-phenethylamine (1.0 g, 3,2 mmol) and3,3-tetramethyleneglutaric anhydride (0,543 g, 3,2 mmol) in pyridine (10ml) was heated under reflux under an atmosphere of nitrogen for 21 h,cooled to room temperature, and evaporated in vacuo to give a brown oil.A solution of the oil in acetic anhydride (15 ml) was heated underreflux for 21 h, cooled to room temperature, and evaporated in vacuo.The residue in water was basified with saturated aqueous ammonia andextracted with ethyl acetate (2×50 ml). The extracts were washed withwater (100 ml), dried (MgSO₄), and evaporated in vacuo. The residue waspurified by chromatography [silica; hexane-ethyl acetate (3:2)] to givethe product free base a yellow oil (0.82 g).

The oil was dissolved in methanol (5 ml) and the solution acidifed withethereal hydrogen chloride, evaporated in vacuo, and the crystalstriturated with ether to give the dihydrochloride salt of the product(0.63 g) m.p. 203°-206° (Found: C, 62.9; H, 7.0; N, 7.9;.C₂₈ H₃₅ N₃O₃.2HCl requires C, 62.5; H, 7.1; N, 8.0%).

EXAMPLE 51 2,3,4,5,6,7-Hexahydro-1-{2-[1-(4-(2-methoxyphenyl)piperazinyl)methyl]-3-phenylpropanoyl}-1H-azepine

This compound was prepared from the acid of Example 2 (20 g, 5.65 mmol),1,1'-carbonyldiimidazole (0.92 g, 5.7 mmol), and hexahydro-1H-azepine(0.62 g, 6.3 mmol) using the method outlined in Example 6 and the crudeproduct was purified by chromatography [silica; ethyl acetate-hexane(1:1)]. The sesquihydrochloride salt of the product was isolated ascrystals (0.96 g), m.p. 195°-195.5° (from ethyl acetate).

(Found: C, 65.9; H, 8.0; N, 8.5. C₂₇ H₃₇ N₃ O₂.11/2HCl requires C, 66.1;H, 7.9; N, 8.6%)

EXAMPLE 52 N-Cycloheptyl-2-{1-[4-(2-methoxyphenyl)piperazinyl]methyl}-3-phenylpropanamide

This compound was prepared from the dihydrochloride salt of the acid ofExample 2 (2.2 g, 4.5 mmol), 1,1'-carbonyldiimidazole (0.8 g, 4.9 mmol),and cycloheptylamine (0.56 g, 4.9 mml) in the presence of triethylamine(1.18 g, 11.7 mmol) using the method outlined in Example 51. Thedihydrochloride salt of the product was isolated as off white crystals(0.91 g), m.p. 178.5°-181.5°.

(Found: C, 64.1; H, 7.9; N, 8.0. C₂₈ H₃₉ N₃ O₂.2HCl requires C, 64.4; H,7.9; N, 8.0%).

EXAMPLE 53 (a)1-{1-[4-(2-Methoxyphenyl)piperazinyl]}-3,3-dimethylbutan-2-ol

A mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (34.5 g, 0.16mol), 3,3-dimethyl-1,2-epoxybutane (20 g, 0.2 mol) triethylamine (20 g),and acetonitrile (120 mol) was heated at reflux for 56 h. The reactionwas then diluted with water (500 ml) and extracted with ether (200 ml).The extract was washed with water (2×200 ml), dried (sodium sulphate),and evaporated in vacuo. The residue was dissolved in ethanol (100 ml)and ether (50 ml) and the solution acidified with ethanolic hydrogenchloride to precipitate the dihydrochloride salt of the product (26.1g), m.p. 243°-245°.

(b)2-{1-[1-(4-(2-Methoxyphenyl)piperazinyl]-3,3-dimethyl}butyl-4-fluorobenzoate

The dihydrochloride salt of the product of Example 53(a) (1.0 g, 2.7mmol), triethylamine (0.4 g, 3.8 mmol), and 4-fluorobenzoyl chloride(0.6 g, 3.8 mmol) in dichloromethane (15 ml) was stirred at roomtemperature for 18 h and the reaction mixture concentrated in vacuo. Theresidue was purified by chromotagraphy [silica; ethyl acetate-hexane(1:1)] to afford an oil which was dissolved in ethyl acetate andacidified with ethereal hydrogen chloride to afford the dihydrochloridesalt of the product, m.p. 232.5°-234°.

(Found: C, 58.9; H, 6.9; N, 5.6. C₂₄ H₃₁ FN₂ O₃ requires C 59.1; H, 6,8;N, 5.8%).

EXAMPLE 54 N-Cyclopropyl-2-{1-[4-(2-methoxyphenyl)piperazinyl]methyl}-3-phenylpropanamide

This compound was prepared from the acid of Example 2 (2.5 g, 7.0 mmol),1,1'-carbonyldiimidazole (1.2 g, 7.4 mol) and cyclopropylamine (0.44 g,7,7 mmol) using the method outlined in Example 51. The hydrochloridequarter hydrate salt of the product was isolated as a powder (2.12 g,),m.p. 169°-170.5°

(Found: C, 66.3;H 7.6; N, 9.4. C₂₄ H₃₁ N₃ O₂.HCl.1/4H₂ O requires C,66.3; H, 7.5; N, 9.7%).

EXAMPLE 55 (a) α-{[1-(4-Phenylpiperazinyl)]methyl}benzeneacetic acid

1-Phenylpiperazine and atropic acid in ethanol is heated under refluxfor 18 h, cooled to room temperature, and evaporated in vacuo. The solidis triturated with acetone to give the title product.

(b) N-Cyclopropyl-2-phenyl-3-[1-(4-phenylpiperazinyl)]propanamide

This compound is prepared by the reaction of the product of Example55(a) with 1,1'-carbonyldiimidazole and cyclopropylamine following theprocedure outlined in Example 6.

EXAMPLE 56 N-cyclohexyl-2-phenyl-3-{1-[4-(3-trifluoromethylphenyl)piperazinyl]}propanamide

A solution of the product of Example 4 andN-(3-trifluoromethylphenyl)piperazine is heated in propanol in thepresence of a small quantity of acetic acid as catalyst to give thetitle product.

EXAMPLE 57 (a) 2-{1-[4-(1-Naphthyl)piperazinyl]}-1-phenylethanol

Styrene oxide and 1-(1-naphthyl)piperazine in acetonitrile are heatedunder reflux. Concentration in vacuo and purification by chromatography(silica; ethyl acetate) gives the product.

(b) 2-{1-[4-(1-Naphthyl)piperazinyl]}-1-phenylethylcyclohexananecarboxylate

This compound is prepared by the reaction of the product of Example57(a) with cyclohexanecarbonyl chloride using the method described inExample 40

EXAMPLE 58 (a) 2-{1-[4-(3-Chlorophenyl)piperazinyl]}-1-phenyl ethanol

The reaction of styrene oxide and 1-(3-chlorophenyl)piperazine gives thetitle compound using the method outlined in Example 57(a).

(b)O-{2-[1-(4-(3-Chlorophenyl)piperazinyl)]-1-phenylethyl}-N-phenylcarbamate

The above compound is prepared following the procedure of Example 38 butsubstituting phenylisocyanate for cyclohexylisocyanate and the productof Example 58 (a) for2-[4-(2-methoxyphenyl)piperazin-1-yl]-1-phenylethanol.

EXAMPLE 59(R)-N-[2-[1-[4-(2-Methoxyphenyl)piperazinyl]]-1-phenylethyl]cyclohexanecarboxylic acid amide

A stirred solution of(R)-2-(1-(4-(2-methoxyphenyl)piperazinyl))-1-phenylethylamine (14.0 g,45.0 mmol) in dichloromethane (250 ml) was treated dropwise withcyclohexanecarbonyl chloride (7.0 ml, 52.4 mmol) in dichloromethane (25ml) under argon, after 18 h washed with 0.3N-NaOH (300 ml) and water(500 ml), dried (MgSO₄), and evaporated in vacuo. The solid was purifiedby recrystallisation from ethyl acetate -cyclohexane to give colourlesscrystals (10.5 g) [α]_(D) ²⁶ =21.5° (CHCl₃, 1%).

The crystals were suspended in methanol (50 ml) and the suspensionacidified with ethereal hydrogen chloride to give a solution.Evaporation in vacuo and trituration with ether gave the title compoundas the dihydrochloride quarter hydrate (11.5 g) m.p. 190°-200° C.(Found: C, 62.4; H, 7.3; N, 8.3. C₂₆ H₃₅ N₃ O₂ 2HCl.1/4H₂ O) requires C,62.6; H, 7.6; N, 8.4%).

[α]_(D) ²⁶ =-48.4° (MeOH, 1%).

I claim:
 1. A compound of the formula ##STR19## or a pharmaceuticallyacceptable acid addition salt thereof wherein n is one of the integers 1or 2,R is hydrogen or lower alkyl, R¹ is a phenyl or naphthyl radicaloptionally substituted by one or more lower alkyl, lower alkoxy,halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano, amino,(lower)alkylamino or di(lower)alkylamino substituents; or a mono orbicyclic heteroaromatic radical having 5 to 10 ring atoms, theheteroaromatic radical having, as heteroatoms one or two nitrogen atomsand being optionally substituted by one or more lower alkyl, loweralkoxy, halogen, trifluoromethyl, nitro, carboalkoxy, carboxamido,cyano, amino, (lower)alkylamino or di(lower)alkylamino substituents, R²is hydrogen or lower alkyl, R³ is an aryl radical, or anaryl(lower)alkyl radical, in which the aryl radical is a phenyl ornaphthyl radical optionally substituted by one or more lower alkyl,lower alkoxy, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido,cyano, amino, (lower)alkylamino or di(lower)alkylamino substituents, R⁴is hydrogen or lower alkyl, R⁶ is cycloalkyl of 3 to 12 carbon atoms oraryl(lower)alkyl where the aryl radical is a phenyl or naphthyl radicaloptionally substituted by one or more lower alkyl, lower alkoxy,halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano, amino,(lower)alkylamino or di(lower)alkylamino substituents.
 2. A compound asclaimed in claim 1 in which R¹ is a phenyl radical optionallysubstituted by one or more lower alkoxy, halogen, trifluoromethyl,nitro, carbalkoxy, carboxamido, cyano, amino, (lower)alkylamino ordi(lower)alkylamino substituents.
 3. A compound as claimed in claim 1 inwhich R³ is a phenyl radical optionally substituted by one or more loweralkoxy, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano,amino, (lower)alkylamino or di(lower)alkylamino substituents.
 4. Acompound as claimed in claim 1 which is(R)-N-[2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethyl]cyclohexanecarboxylic acid amide or a pharmaceutically acceptable salt thereof. 5.A compound as claimed in claim 1 which is(S)-N-[2-[1-[4-(2-methoxyphenyl)piperazinyl]]-1-phenylethyl]cyclohexanecarboxylic acid amide or a pharmaceutically acceptable salt thereof. 6.A pharmaceutical composition for use in treating depression or anxietyin a mammal, comprising an amount of a compound of claim 1 effective toalleviate depression or anxiety in association with a pharmaceuticallyacceptable carrier.
 7. A compound of the formula ##STR20## or apharmaceutically acceptable acid addition salt thereof wherein n is oneof the integers 1 or 2,R is hydrogen or lower alkyl, R¹ is a phenyl ornaphthyl radical optionally substituted by one or more lower alkyl,lower alkoxy, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido,cyano, amino, (lower)alkylamino or di(lower)alkylamino substituents; ora mono or bicyclic heteroaromatic radical having 5 to 10 ring atoms, theheteroaromatic radical having, as heteroatoms one or two nitrogen atomsand being optionally substituted by one or more lower alkyl, loweralkoxy, halogen, trifluoromethyl, nitro, carboalkoxy, carboxamido,cyano, amino, (lower)alkylamino or di(lower)alkylamino substituents, R²is hydrogen or lower alkyl, R³ is an aryl radical, or anaryl(lower)alkyl radical, in which the aryl radical is a phenyl ornaphthyl radical optionally substituted by one or more lower alkyl,lower alkoxy, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido,cyano, amino, (lower)alkylamino or di(lower)alkylamino substituents, R⁴is hydrogen or lower alkyl, R⁶ is --CHR⁷ R⁸ where R⁷ and R⁸ are eachhydrogen or lower alkyl,provided that when R¹ is pyrimidinyl, R² ishydrogen and R³ is phenyl or optionally substituted phenyl, then n mustbe
 2. 8. A compound as claimed in claim 7 in which R¹ is a phenylradical optionally substituted by one or more lower alkoxy, halogen,trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano, amino,(lower)alkylamino or di(lower)alkylamino substituents.
 9. A compound asclaimed in claim 7 in which R³ is a phenyl radical optionallysubstituted by one or more lower alkoxy, halogen, trifluoromethyl,nitro, carbalkoxy, carboxamido, cyano, amino, (lower)alkylamino ordi(lower)alkylamino substituents.
 10. A pharmaceutical composition foruse in treating depression or anxiety in a mammal, comprising an amountof a compound of claim 7 effective to alleviate depression or anxiety inassociation with a pharmaceutically acceptable carrier.